GLP-1 Analogs: An Emerging Drug Therapy for Glycemic Control

Pamela L. Havrilla, PharmD, and Scott R. Drab, PharmD, CDC, BC-ADM
Published Online: Wednesday, October 1, 2008

Dr. Havrilla is a critical care specialty resident at University of Pittsburgh Medical Center. Dr. Drab is an assistant professor of Pharmacy & Therapeutics at University of Pittsburgh School of Pharmacy and director of the University Diabetes Care Associates.


In the United States, the incidence of diabetes is reaching epidemic proportions. According to the Centers for Disease Control and Prevention, 23.6 million people or 7.8% of the US population, have diabetes. In addition, 25.9% of adults are estimated to have prediabetes, based on fasting blood glucose test results. The combined incidence of diabetes and prediabetes suggests that approximately 34% of the US population is currently at risk for diabetes-related medical complications.1

The development of diabetes in America's youth seems to be on the rise. Results from the 2005-2006 National Health and Nutrition Examination Survey indicate that 16% to 17% of children and adolescents aged 2 to 19 have a body mass index greater than or equal to the 95th percentile of their age and sex-specific group, which is almost double the number of children in this category 2 decades ago.1,2 Worldwide, the rise in type 2 diabetes is occurring in parallel with the increasing prevalence of obesity in children.3,4

Diabetes Risk Factors and Complications

Risk factors for developing diabetes include a family history of diabetes, ethnicity (risk is increased for Asians, Hispanics, and African Americans), obesity, central fat distribution, and inactivity.5 Obesity may be one of the most important of these risk factors, as it induces resistance to insulinmediated peripheral glucose uptake, an important component of type 2 diabetes. The reversal of obesity decreases the risk of type 2 diabetes and can improve glycemic control in patients with established disease.5

Complications of diabetes include coronary heart disease (CHD), which is a major cause of morbidity and mortality for this patient population. Patients with diabetes possess more cardiovascular risk factors, such as hypertension, obesity, lipid abnormalities, and elevated plasma fibrinogen than do individuals without diabetes.6 The National Cholesterol Education Program report considers type 2 diabetes to be a CHD equivalent. This brings diabetes to the highest risk category for CHD.7

What Is GLP-1?

Glucose homeostasis is a complicated process that involves insulin, as well as amylin, glucagon, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP). GLP-1 is a peptide secreted by L cells in the intestines with the ingestion of food. It increases glucose-dependent insulin secretion from beta cells in the pancreas, decreases glucagon secretion in the liver, inhibits gastric emptying, decreases food intake by increasing satiety, and improves beta cell function.8,9 Postprandial GLP-1 concentrations and the insulin secretory response to GIP are reduced in patients with type 2 diabetes and in patients with impaired glucose tolerance.10,11

Knowledge of the role of GLP-1 and GIP in normal glucose homeostasis has led to the development of new therapeutic agents, such as the GLP-1 analogs. This medication class affects glucose control through several mechanisms that are similar to the naturally produced hormone GLP-1. One of the newest medications within this class, the experimental drug liraglutide, not only improves glycemic control but may also have advantages over current therapies. For example, liraglutide acts in a glucose-dependent manner, stimulating insulin secretion only when glucose levels are higher than normal. Furthermore, the risk for hypoglycemia with liraglutide is low, and the potential for beta cell regeneration has been shown in animal models.12

Liraglutide can be administered once daily by subcutaneous injection at interchangeable sites, including the abdomen, upper arm, and thigh, without a clinically significant change in absorption.13 The half-life of liraglutide when administered subcutaneously is 13 hours, as compared with a half-life of less than 2 minutes for endogenously produced GLP-1. It is postulated that self-association of the drug, due to a fatty acid side chain (palmitoyl), delays absorption of liraglutide and prolongs its action.14 The metabolism of liraglutide was found to be similar to that of large peptides, with no single organ being responsible as the major route of elimination.15

Liraglutide: A Review of the Findings

Weight loss in obese patients with type 2 diabetes reduces all risk factors for CHD.16 Several trials have evaluated the effect of liraglutide on weight. In one study, researchers reported that liraglutide decreases postprandial hunger ratings and energy intake in patients.17 This GLP-1 analog was also shown to reduce fat percentage, central adipose tissue, and hepatic steatosis when added to metformin, as compared with glimepiride plus metformin.18 When added to the sulfonylurea glimepiride, liraglutide improved glycemic control by reducing the A1C, producing a greater decrease in body weight than rosiglitazone plus glimepiride. Both results were statistically significant.19

Studies also compared liraglutide to glimepiride, with both being addon therapy to metformin. One study discovered that liraglutide significantly reduced the perceived frequency of hyperglycemia, hypoglycemia, and public distress due to weight, and the other study concluded that liraglutide plus metformin resulted in a comparable reduction of A1C with less hypoglycemic episodes and greater weight loss in the liraglutide group.20,21

When liraglutide was compared with glimepiride as monotherapy for diabetes, liraglutide significantly lowered A1C and resulted in weight loss and fewer episodes of hypoglycemia as compared with patients in the glimepiride arm.22 When compared with insulin glargine as add-on therapy to metformin and a sulfonylurea, the liraglutide group statistically improved glycemic control and reduced body weight as compared with the glargine treatment group.23

Liraglutide has also been shown to improve not only fasting blood glucose levels but also both the absolute and incremental postprandial glucose levels. This impact is postulated to be mediated through a combination of increased insulin secretion coupled with delayed gastric emptying.24 Overall, the effects of liraglutide therapy on weight loss and glycemic control demonstrated in these trials could assist in the weight loss efforts of patients, decrease central adiposity, reduce the number of hypoglycemic episodes, and improve glycemic control.

The reduction of CHD risk factors, as well as effective, safe, and welltolerated therapy, is the cornerstone to improving morbidity and mortality in the diabetic population. High blood pressure is prevalent in the diabetic population and is an additional risk factor for CHD. Liraglutide was found to improve the cardiovascular risk profile by reducing the mean systolic blood pressure in patients.25

If it is approved by the FDA, liraglutide will be made available in a prefilled disposable injection device. This mode of administration has been shown to be a major asset for improving compliance among patients with diabetes. These devices are considered convenient and easy to use, and they provide the patient with additional freedom, which could increase compliance and therefore reduce diabetes-related complications.26

The Pharmacist Can Help

The pharmacist can play a major role in aiding compliance and patient understanding. Counseling sessions can impart better understanding of the medication and its importance. In addition, instruction in the correct injection technique, whether with a syringe and vial or prefilled injection device, is important to ensure appropriate medication use. Not only can a pharmacist increase compliance and provide valuable information to our patients, but we can keep patients abreast of new developments in the treatment of diabetes.

References

  1. CDC. National diabetes fact sheet: general information and national estimates on diabetes in the United States. 2007. www.cdc.gov/diabetes/pubs/pdf/ndfs_2007.pdf Accessed August 13, 2008.
  2. Ogden CL, Carroll MD, Flegal KM: High body mass index for age among US children and adolescents, 2003-2006. JAMA 2008; 299(20): 2401-5.
  3. American Diabetes Association: Standards of medical care in diabetes--2008. Diabetes Care 2008; 31 Suppl 1: S12-54.
  4. Pinhas-Hamiel, O, Zeitler, P. The global spread of type 2 diabetes mellitus in children and adolescents. J Pediatr. 2005; 146:693.
  5. National Diabetes Information Clearinghouse (NDIC).2008. diabetes.niddk.nih.gov/dm/pubs/riskfortype2/index.htm. Accessed August 13 2008.
  6. Taegtmeyer, H, McNulty, P, Young, ME. Adaptation and maladaptation of the heart in diabetes: Part I: general concepts. Circulation 2002; 105:1727.
  7. Third report of the National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III): Final report. US Department of Health and Human Services; Public Health Service; National Institutes of Health; National Heart, Lung, and Blood Institute. Circulation 2002; 106:3143.
  8. Egan, JM, Clocquet, AR, Elahi, D. The insulinotropic effect of acute exendin-4 administered to humans: comparison of nondiabetic state to type 2 diabetes. J Clin Endocrinol Metab. 2002; 87:1282.
  9. Matthews D, Marre M, Le-Thi TD, et al. Liraglutide, a once-daily human GLP-1 analog, significantly improves ?-cell function in subjects with type 2 diabetes. Diabetes. 2008;57(Suppl 1)A150-1, 505-P.
  10. Toft-Nielsen MB, Madsbad S, Holst JJ. Determinants of the effectiveness of glucagon-like peptide-1 in type 2 diabetes. J Clin Endocrinol Metab. 2001; 86:3717-3723.
  11. Nauck MA, Heimesaat MM, Orskov C, et al. Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest. 1993; 91(1):301-7.
  12. Buteau J, El-Assaad W, Rhodes CJ, et al. Glucagon-like peptide-1 prevents beta cell glucolipotoxicity. Diabetologia. 2004;47(5):806-15.
  13. Kapitza C, Flint A, Spitzer H, et al. The effect of three differenct injection sites on the pharmacokinetics of the one-daily human GLP-1 analogue liaglutide. Diabetes. 2008; 57(Suppl 1):A593, 2146-PO.
  14. Steensgaard DB, Thomsen JK, Olsen HB, et al. The molecular basis for the de9Suppl 1layed absorption of once dialy human GLP-1 analoge, liraglutide. Diabetes. 2008; 57(Suppl 1):A164.
  15. Hellenberg H, Malm-Erkefalt M, Bjornsdottir I, et al. Metabolism and excretion of [PaI-3H]-liraglutide in human healthy subjects. Diabetes. 2008;57(Suppl 1):A581-2,2107-P.
  16. Buse JB, Ginsberg HN, Bakris GL, et al. Primary prevention of cardiovascular diseases in people with diabetes mellitus. A scientific statement from the American Heart Association and the American Diabetes Association. Diabetes Care. 2007;30(1):162-172.
  17. Flint A, Kapitza C, Hindsberger C, et al. The once-daily human GLP-1 analogue liraglutide decreases postprandial Hunger and energy intake. Diabetes. 2008;57(Suppl 1):A165, 555-P.
  18. Jendle J, Nauck MA, Matthews D, et al. Liraglutide, a once-daily human GLP-1 analog, reduces fat percentage, visceral and subcutaneous adipose tissue and hepatic stenosis compared with glimepiride when added to metformin in subjects with type 2 diabetes. Diabetes. 2008;(Suppl 1):A32, 106-OR.
  19. Marre Michel, Shaw J, Brandle m, et al. Liraglutide, a once-daily human GLP-1 analog, added to a sulfonylurea (SU) offers significantly better glycemic control and favorable weight change compared with rosiglitazone and SU combination therapy. Diabetes. 2008;57(Suppl 1):A4,13-OR.
  20. Frid A, Nauck MA, Hermansen K, et al. Evaluation of patient reported outcomes in subjects with type 2 diabetes treated with the once-daily human GLP-1 analog liraglutide or glimepiride, both as add on to metformin. Diabetes. 2008;57(Suppl 1):A574.
  21. Nauck MA, Frid A, Hermansen K, et al. Liraglutide, a once-daily human GLP-1 analog, in type 2 diabetes provides similar glycemic control with reduced body weight compared with glimepiride when added to metformin. Diabetes. 2008;57(Suppl 1):A150,504-P.
  22. Garber A, Henry R, Ratner R, et al. Significantly better glycemic control and weight reduction with liraglutide, a once daily GLP-1 analog, compared with glimepiride: All as monotherapy in type 2 diabetes. American Diabetes Association. scientificsessionsdiabetes.org/index.cfm~. Accessed August 17, 2008.
  23. Russell-Jones D, Vaag A, Schmitz O, et al. Significantly better glycemic control and weight reduction with liraglutide, a once-daily human GLP-1 analog, compared with insulin glargine:All as add-on to metformin and a sulfonylurea in type 2 diabetes. Diabetes. 2008;57(Suppl 1):A159-60,536-P.
  24. Flint A, Kapitza C, Hindsberger C, et al. The once-daily human GLP-1 analogue liraglutide improves both absolute and baseline corrected postprandial glucose levels. Diabetes. 2008;57(Suppl 1): A165, abs556-P.
  25. Colagiuri S, Frid A, Zdravkovic M, et al. The once-daily human GLP-1 analog liraglutide reduces systolic blood pressure in patients with type 2 diabetes. Diabetes. 2008;57(Suppl 1):A164-5, abs 554-P.
  26. Bohannon NJ. Insulin delivery using pen devices. Simple-to-use tools may help young and old alike. Postgraduate Medicine. 1999;106(5):57-8,57-8, 61-4, 68.

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